Serotonin, a neurotransmitter that carries signal in the brain and nerves, plays a very important role in central nervous system (CNS) dysfunction, especially in anxiety, depression, aggression and impulsivity. Regulation of the central nervous system dysfunction is possible either by antagonistic or agonistic action on a certain type of the serotonin receptors. To date, at least 14 different serotonin receptors have been identified. These receptors can be divided into distinct families—denoted 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7, with subtypes in each family denoted by letters such as a, b and c. Central serotonergic neurons are located in the raphe nuclei in the brain stem. The 5-HT1A receptor is a G-protein-coupled receptor widely distributed in regions that receive serotonergic input from the raphe nuclei: the frontal cortex, septum, amygdala, hippocampus, and hypothalamus. In these cortico-limbic regions, 5-HT1A is distributed post-synaptically. The 5-HT1A receptor also serves as the predominant (somatodendritic) autoreceptor of the raphe nuclei, reducing the firing rate of neurons (the amount of serotonin released per action potential), the synthesis of the neurotransmitter, and thus by implication, the serotonergic activity of its projection areas. Activation of the presynaptic 5-HT1A, receptor may also indirectly reduce serotonergic transmission through the inhibition of tyrosine hydroxylase synthesis, as well as the activity of glutamatergic pathway that originates in the medial prefrontal cortex and projects to the raphe nuclei (Jonathan Savitz et al., “5-HT1A receptor function in major depressive disorder,” Prog. Neurobiol., 2009, 88(1): 17-31).
Depression is the most important of all therapeutic indications related to 5-HT disorder since it is the fourth leading burdensome disease in the world according to the World Health Organization. By 2020, depression is projected to rank second in disability-adjusted life years (Bromet E et al., “Cross-national epidemiology of DSM-IV major depressive episode,” BMC Med., 2011, 9: 90).
Historically, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) revolutionized the pharmacologic treatment of mood disorders in the 1950s, mostly by blocking neurotransmitter (dopamine, norepinephrine, and serotonin). However, the non-selectivity and undesirable side effect eventually limited their use. In 1980s, the discovery of selective serotonin reuptake inhibitors (SSRIs) changed the landscape. As a class, the SSRIs boast similar efficacy compared to the TCAs, and an improved AE profile with less tendency for toxicity in overdose (Sarko J, “Andidepressant, old and new. A review of their adverse effects and toxicity in overdose,” Emerg. Med. Clin North Am., 2000, 18 (4): 637-54).
Conventional SSRIs therapeutically increase available serotonin by inhibiting its reuptake and modulating its transmission. Administration of SSRIs also pleiotropically stimulates pre-synaptic 5-HT1A autoreceptors, which acutely decreases the release of serotonin and subsequently reduces serotonin concentrations in the synapse. After chronic administration, the stimulation of the 5-HT1A autoreceptors is overcome via desensitization and the SSRIs is able to normalize serotonergic transmission. It is postulated that this stimulation of the autoreceptor is the causative factor in the delayed therapeutic effect of the SSRIs (Celada P et al., “The therapeutic role of 5-HT1A and 5-HT2A receptors in depression,” J Psychiatry Neurosci., 2004, 29(4): 252-65). Thus, overriding the negative feedback effect of 5-HT1A autoreceptors antagonists holds the promise of increasing and accelerating clinical antidepressant effects.
Compared to SSRIs, 5-HT1A receptor agonists or partial agonists act directly on postsynaptic serotonin receptors to increase serotonin neurotransmission during the SSRI latency effect period. Feiger and Wilcox demonstrated that the buspirone and gepirone were clinically effective 5-HT1A partial agonists (Feiger, A, Psychopharmacol. Bull., 1996, 32: 659-65). The addition of buspirone to standard SSRI treatment produced a marked improvement in patients previously unresponsive to standard treatment for depression (Dimitriou, E. J., Clin. Psychopharmacol., 1998, 18: 465-9).
Provided herein are novel compounds believed to have clinical use in treating CNS disorders through selectively inhibiting serotonin reuptake and/or acting as 5-HT1A receptor agonists. The compounds disclosed herein are also believed to provide an improvement in potency, pharmacokinetic properties, and/or toxicity profile over certain counterparts found in the art.